Molecure, a clinical stage biotechnology company, discovers and develops breakthrough small molecule drugs that modulate unexplored protein targets and novel RNA to treat cancer, fibrotic and inflammatory diseases.
Our exceptional in-house medicinal chemistry and biology capabilities, along with novel target insights gained from leading academic centers, have allowed us to create a broad pipeline of drug candidates targeting unique and unexplored protein targets. Our lead assets, OATD-01 and OATD-02, are in clinical development for the treatment of sarcoidosis and solid tumors respectively.
In addition, we are developing a unique RNA platform, to discover small molecule compounds that interact directly with the mRNA of disease-related proteins, with significant potential across multiple disease areas.
Targeting unexplored proteins
Molecule is discovering and developing first-in-class small molecules in oncology, inflammation and fibrosis that target/interact with selected, unexplored proteins.
We have generated a diverse pipeline consisting of seven distinct programs, validating the strength of our discovery and translational capabilities, including:
- 1 program in clinical development and Phase II ready with another molecule entered the clinic in Q1 2023
- 5 programs in preclinical development, spanning 4 unchartered novel target families (arginases, chitinases, deubiquitinases as well as one undisclosed target).
OATD-01, Molecure’s lead candidate, is an oral, once-daily, first-in-class highly selective CHIT1 inhibitor for the treatment of sarcoidosis. CHIT1, or Chitotriosidase, is produced by pathologically activated macrophages, and is the primary active chitinase in the lung.
OATD-01 is potentially a disease modifying therapy that could transform the standard of care.
Multiple published studies, as well as Molecure’s own translational data has shown CHIT1, the target of OATD-01, to be upregulated in sarcoidosis and the level of upregulation to be correlated with disease severity. In sarcoidosis patients, the over-expression of CHIT1, is also a marker of disease progression.
Phase I studies have demonstrated OATD-01 to be safe and to have a novel therapeutic mechanism of action, simultaneously targeting inflammation and fibrosis.
Phase II studies with OATD-01 in sarcoidosis patients are expected to start in the second half of 2023.
Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis
OATD-01 has demonstrated potent anti-inflammatory and antifibrotic effects in various disease models and has high therapeutic potential in diverse inflammatory and fibrotic diseases with high unmet medical needs such as sarcoidosis, as well as idiopathic pulmonary fibrosis and NASH where efficacy was demonstrated in preclinical models. Possible further respiratory indications include inflammatory asthma, COPD, other Interstitial Lung Diseases (scleroderma and rheumatoid arthritis-associated fibrosis) or in non-pulmonary diseases, diabetic nephropathy, ALS and Crohn’s disease.
OATD-01 was successfully out-licensed to Galapagos NV in 2020 for the global development and commercialization of the product. As a result of a portfolio review by Galapagos in 2022, Molecure regained full rights to OATD-01 together with all the related IP and know-how.
Molecure is now focused on developing OATD-01 to realise its significant clinical potential and is looking to advance this asset into a Phase 2 clinical trial in patients with sarcoidosis in 2023.
OATD-01 in Sarcoidosis/The relevance of Chitinase inhibitors in Sarcoidosis
Sarcoidosis is a systemic inflammatory disease that is characterized by the formation of small clumps of inflammatory cells, called granulomas in various organs, mainly the lungs and the lymphatic system. Its cause is unknown.
Sarcoidosis is a global disease, affecting both men and women with a prevalence of about 5–50 in 100 000, with 70% of the patients aged between 25 and 45 years.
The most severe and frequent complication of sarcoidosis is the occurrence of pulmonary fibrosis. This is usually associated with significant impairment of pulmonary function, whereby granulomatous inflammation leads to pulmonary fibrosis. The development of pulmonary fibrosis is associated with significant increase in morbidity and can be fatal.
There is currently no cure for sarcoidosis and existing treatments such as corticosteroids only modify/impede the development of granuloma formation and come with a significant range of side effects. There is also little evidence of extended therapeutic efficacy.
During preclinical development, OATD-01 has been shown to significantly decrease the disease severity, to suppress the development of granulomas and reduce inflammation in the lungs of treated animals.
Our second generation CHIT1 inhibitor program
CHIT1 is also involved in the pathology of various diseases with inflammatory and fibrotic components, including non-alcoholic steatohepatitis (NASH), and potentially a broad spectrum of neurological diseases that are characterized by excessive activation of inflammatory cells in the brain (neuroinflammation).
Molecure is developing other selective CHIT1 inhibitors, structurally different from OATD-01, which have been selected for proof-of-concept validation in models of these diseases.
Arginase 1 (ARG1) and Arginase 2 (ARG2) are validated targets that have been found on a variety of tumor types where their increased activity correlates with more advanced disease and worse clinical prognosis due to diminished arginine levels.
Our second proprietary candidate, OATD-02 is the first and only dual acting, highly potent arginase inhibitor in cancer development, involved in both tumor immunity and metabolism. It has been selected as a clinical candidate for the potential treatment of a broad range of tumors in combination with other anti-cancer therapeutics.
OATD-02 is on the stage of Phase I clinical trials.
Deubiquitinase (DUB) Inhibitor Program – USP7
Molecure is developing inhibitors of DUBs, including a selective inhibitor of ubiquitin specific protease 7 (USP7), whose high expression is seen to be aberrant in a number of tumor indications, promoting oncogenesis. USP7 regulates the levels of multiple proteins involved in the cell cycle and the immune response, particularly in the homeostasis of p53, a tumor suppressor protein and regulator of the cell cycle.
Molecure has identified a lead molecule OAT-4828, a potent and selective USP7 inhibitor, which demonstrates safety and efficacy in selected models of cancer. The mode of action of USP7 inhibitor is based on stimulating the body’s immune response against the cancer and via direct inhibition of cancer cell proliferation combined with apoptosis. The pharmacological profile of Molecure’s nominated clinical candidate will enable oral dosing in patients.
Ubiquitination, the addition of ubiquitin to a substrate, is a post translational modification critical to cell homeostasis. Expression of deubiquitinases or ubiquitin-specific proteases (DUBs/USPs), enzymes involved in the deubiquitination of proteins, can be abnormal in tumors and the tumor microenvironment, making DUBs a potential important group of targets for anticancer therapeutic agents.
YKL-40 which belongs to the chitinase-like proteins (CLPs) family, is a secreted protein with homologies to chitinases but devoid of catalytic function.
High levels of YKL-40 are linked to poor prognosis, progression and the severity of various inflammatory disorders and numerous types of cancer. The protein is produced and secreted by immune cells (especially macrophages, neutrophils) and various structural cells like fibroblasts, smooth muscle, epithelial, endothelial and also cancer cells.
Unique RNA platform
Molecure is developing a unique RNA platform to discover small molecule compounds that interact directly with the mRNA of disease-related proteins. By modulating mRNA biological function and affecting its translation we are able to discover medicines with a novel mechanism of action.
This approach offers access to potentially thousands of new therapeutic targets, which were previously considered ‘undruggable’.
From the estimated ∼20 000 proteins that comprise the human proteome, only 15% are considered “druggable”. This is because just a fraction of proteins that are potential drug targets i.e. are linked to a disease, have the ability to bind a small molecules.
As a result, the human transcriptome (mRNA molecules coding those proteins) is underexploited as a new source of therapeutic targets and for long considered ‘undruggable’ via conventional approaches.
Molecule has developed a bioinformatics platform and positions it to outperform the standard methods used in discovery of small molecule drugs targeting RNA.
Molecure’s workflow consists of:
- Identifying unique, stable and functional motifs within mRNA of clinically relevant genes associated with disease-related functions and previously undruggable targets, using exclusive algorithms. Those predicted motifs are then confirmed at a single nucleotide resolution by NGS and chemical probing.
- Using a combination of AI and dynamic NMR assessment, focusing on those mRNA motifs with sufficient structural sophistication that make it likely that high affinity and specificity small molecule binding sites can be mapped out.
- Using a combination of virtual modelling and tradition medicinal chemistry, screening and refining hit and lead compounds and further assessment of their potency in vitro and in vivo to discover new drug-like molecules interacting with mRNA.
Molecure’s current aim is to provide the industry with an engine to identify hit compounds, demonstrating druggability of mRNA targets, which opens tremendous scientific and medical opportunities.
The development of Molecure’s mRNA platform is being supported by an exclusive research collaboration agreement with the International Institute of Molecular and Cell Biology (IIMCB) in Warsaw.
This collaboration provides the company with access to world-leading and unique bioinformatics tools developed by the Laboratory of Bioinformatics and Protein Engineering (LBIB) at IIMCB, headed by prof. Janusz Bujnicki.